Purpose: GCRC Protocol 697 entitled "Atherosclerosis Studies" enabled the procurement of fasting human plasma for isolation of lipoproteins. The lipoproteins have been used principally for investigation of the chemistry of lipoprotein oxidation. Methods: In collaboration with Dr. Ned Porter of the Department of Chemistry we performed studies to determine the major regioisomeric hydroperoxides and alcohols formed during the early stages of LDL and HDL oxidation initiated by the thermolabile azo free radical initiator 2,2'-azobis(2-amidinopropane) dihydrochloride. Results: After a lag time of 1 hour, significant amounts of chol-18:2-OOH and lower levels of chol-18:2-OH begin to form. At this time approximately 90% of the initial alpha- tocopherol is still present in LDL. In the early phase only 13- and 9-cis,trans-chol-18:2-OOH are formed. After depletion of antioxidants, principally alpha-tocopherol, the thermodynamic products - trans,trans-chol-18:2-OOHs - were formed in equal abundance to the cis,trans isomers. In addition to these results, this study also established HPLC methodology for the direct quantitation of specific cholesteryl ester hydroperoxides. Current work is continuing to examine hydroperoxides fromed from arachidonic acid in LDL and HDL. In other ongoing work, human plasma lipoprotein preparations have been compared to lipoproteins derived from cerebrospinal fluid (CSF). In CSF, the major apolipoprotein species are apoE and apoA-I. CSF apoE-containing lipoproteins were shown to be larger than CSF apoA-I-containing lipoproteins, but with considerable overlap. The sizes of some CSF apoE lipoproteins were comparable to plasma LDL. The results are interpreted to suggest that both apoA-I and apoE function in cholesterol redistribution in brain. Significance: The significance of chemical studies on lipoprotein oxidation relates to our longstanding interest in the development of lipid-rich core in human atherosclerosis. Lipoprotein oxidation is a prominent feature in a microenvironment where cellular toxicity and survival responses are important. The understanding of the tissue destructive aspect of atherosclerosis has been hampered by a lack of complete knowledge concerning chemical and cellular aspects of lipoprotein modification. This destructive aspect is already present at the time of lesion transition from fatty streak (Type II lesion) to intermediate lesion (Type III) and then to the fibrous plaque (Type IV). In advanced atherosclerosis, the effect of tissue destruction is to weaken the arterial intima leading to plaque rupture, with consequent rapid thrombosis and often arterial occlusion causing heart attack or stroke.